The aim of the study was to verify the effects of the administration of an inhibitor of the release of endogenous vasodilators together with a vasoconstrictor agent in patients with hepatorenal syndrome (HRS). This new medical perspective was compared with a traditional medical approach for HRS, such as the infusion of nonpressor doses of dopamine to produce renal vasodilation. Thirteen patients with type 1 HRS were enrolled in the study. Five of them were treated with the oral administration of midodrine and the parenteral administration of octreotide. In addition, the patients received 50 to 100 mL of 20% human albumin solution daily for 20 days. Midodrine and octreotide were dosed to obtain a stable increase of at least 15 mm Hg of mean arterial pressure. Eight patients were treated with the intravenous administration of nonpressor doses of dopamine (2-4 g/kg/min) and the same daily amount of albumin. After 20 days of treatment with midodrine and octreotide, an impressive improvement in renal plasma flow (RPF), glomerular filtration rate, and urinary sodium excretion was observed in patients. This was accompanied by a significant reduction in plasma renin activity, plasma vasopressin, and plasma glucagon. No side effects were observed. Three patients were discharged from the hospital. One of them successfully underwent liver transplantation. One of the two remaining patients is still alive after 472 days with a preserved renal function, and the other died from terminal liver failure after 76 days. One of the two patients who were not discharged from the hospital successfully underwent liver transplantation, and the other died from pneumonia after 29 days. Seven out of eight patients who were treated with dopamine experienced a progressive deterioration in renal function and died during the first 12 days. Only one patient recovered renal function and underwent liver transplantation. In conclusion, the long-term administration of midodrine and octreotide seems to be an effective and safe treatment of type 1 HRS in patients with cirrhosis. (HEPATOLOGY 1999;29:1690-1697.)Hepatorenal syndrome (HRS) occurs in 18% of cirrhotic patients with ascites. HRS is characterized by intense vasoconstriction, low glomerular filtration rate (GFR), preserved tubular function, and normal renal histology. 1 The diagnostic criteria of HRS have been recently reviewed, and HRS has been classified on a clinical basis into two different types: type 1 characterized by rapidly progressive renal function impairment and type 2 in which renal failure does not have a rapidly progressive course. 2 From a pathophysiological point of view HRS is considered to be the extreme expression of a reduced effective circulating volume because of arteriolar vasodilation, particularly in the splanchnic area. 3 Consequently, the extreme increase in the activity of both renin-angiotensin and sympathetic nervous system as well as the elevated circulating levels of endothelin are the most likely cause of HRS. [4][5][6][7][8][9]

The effects of the acute administration of arterial vasoconstrictors on renal plasma flow (RPF) and urinary sodium excretion (UNaV) in cirrhotic patients with ascites with or without hepatorenal syndrome (HRS) are still controversial. As a consequence, vasoconstrictors are not actually used in the treatment of renal sodium retention or HRS in these patients, regardless of the several lines of evidence suggesting that these renal functional abnormalities are related to a marked arterial vasodilation. The lack of an orally available effective arterial vasoconstrictor probably represents a further reason for this omission. Consequently, the present study was made to evaluate the acute effects of the oral administration of midodrine, an orally available ␣-mimetic drug, on systemic and renal hemodynamics and on UNaV in cirrhotic patients with ascites. Mean arterial pressure (MAP), heart rate (HR), cardiac index ( The improvement in systemic hemodynamics, which was also maintained during the the 3-to 6-hour period after midodrine administration, was accompanied by a significant increase in RPF (541.5 ؎ 43.1 vs. 385.7 ؎ 39.9 mL · min ؊1 ; P F .005), GFR (93.1 ؎ 6.5 vs. 77.0 ؎ 6.7 mL · min ؊1 ; P F .025), and UNaV (92.7 ؎ 16.4 vs. 72.2 ؎ 10.7 Eq · min ؊1 ; P F .025). In addition, a decrease in PRA (5.33 ؎ 1.47 vs. 7.74 ؎ 2.17 ng · mL ؊1 · h; P F .05), ADH (1.4 ؎ 0.2 vs. 1.7 ؎ 0.2 pg · mL ؊1 ; P F .05), and NOx (33.4 ؎ 5.0 vs. 49.3 ؎ 7.3 mol ؊1 ; P F .05) was found. In patients with HRS, the effects of the drug on the systemic hemodynamics was smaller and shorter. Accordingly, regardless of a significant decrease in PRA (15.87 ؎ 3.70 vs. 20.70 ؎ 4.82 ng · mL ؊1 · h; P F .0025) in patients with HRS, no significant improvement was observed in RPF, GFR, or UNaV. In conclusion, the acute oral administration of midodrine is associated with a significant improvement in systemic hemodynamics in nonazotemic cirrhotic patients with ascites. As a result, renal perfusion and UNaV also improve in these patients. By contrast, midodrine only slightly improves systemic hemodynamics in patients with type 2 HRS, with no effect on renal hemodynamics and renal function. (HEPATOLOGY 1998;28:937-943.)It has been hypothesized that a peripheral arterial vasodilation is the main factor in the pathogenesis of the functional renal abnormalities in patients with cirrhosis. 1-3 Arterial vasodilation is thought to be related to an excess of local or systemic vasodilators such as glucagon, prostacyclin, substance P, vasoactive intestinal peptide, bile acids, and nitric oxide. [3][4][5][6][7] The localization of arterial vasodilation as well as its link with renal sodium retention are also debated. Clinical and experimental studies suggest that the reduction of arterial vascular resistance occurs mainly in the splanchnic area, whereas in many other vascular beds, i.e., in the renal vascular bed, arterial resistance is normal or even increased in cirrhosis with ascites. 8,9 The reflex activation of the neurohumoral pressor systems, sympathetic nervous ...

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Background: Despite hyperaldosteronism being suggested as predisposing to arrhythmias, the relationship between atrial fibrillation and primary aldosteronism remains uncertain. Therefore, we tested the hypothesis that atrial fibrillation is a presentation of primary aldosteronism in hypertensive patients with unexplained atrial fibrillation. Design and methods: The Prospective Appraisal on the Prevalence of Primary Aldosteronism in Hypertensive (PAPPHY) Study recruited consecutive patients with atrial fibrillation and an unambiguous diagnosis of arterial hypertension at three referral centers for hypertension. Results: In a cohort entailing 411 atrial fibrillation patients, we identified 18% (age 61 ± 11 years; 32% women), who showed no known cause of the arrhythmia. A thorough diagnostic work-up allowed us to identify primary aldosteronism in 73 of these patients, i.e. 42% [95% confidence interval (CI) 31.8–53.9]. Subtyping of primary aldosteronism demonstrated that surgically curable forms of primary aldosteronism accounted for 48% of the cases (95% CI 31.9–65.2). The high prevalence of primary aldosteronism was confirmed at sensitivity analyses. Conclusion: These results provided compelling evidence that primary aldosteronism is highly prevalent in hypertensive patients with unexplained atrial fibrillation. Accordingly, they suggest that patients with no identifiable cause of the arrhythmia should be screened for primary aldosteronism to identify those who can be cured or markedly improved with target treatment. Clinical Trial Registration: : https://clinicaltrials.gov, Identifier: NCT01267747.

Intravenous methylprednisolone is used in most liver transplant centers as first-line therapy of acute hepatic cellular rejection in patients who undergo liver transplant. However, no controlled study has been performed to date to define the optimal dose and duration of the steroid regimen. The schedules that actually are used in most transplant centers are drawn from those that were developed empirically for the treatment of acute renal graft rejection. Thus, the aim of the study was to compare two schedules of steroid treatment of acute hepatic cellular rejection among those most widely used. Thirty-eight eligible patients with grade II or III acute hepatic cellular rejection were randomized to receive two different highdose methylprednisolone schedules. Eighteen patients were randomized in group A (intravenous dose of 1,000 mg of methylprednisolone followed by a 6-day taper from 200 to 20 mg/d). Twenty patients were randomized in group B (intravenous dose of 1,000 mg of methylprednisolone for three consecutive days). The response to treatment was evaluated by means of a second liver biopsy. The treatment of group A proved to be more effective than treatment of group B. The resolution of acute hepatic cellular rejection was observed in 83.3% of cases in group A and 50.0% of cases in group B (P < .05). The treatment of group A proved to be safer also than treatment of group B. Patients randomized in group B showed a higher prevalence of infections (90.0% of cases versus 55.5% of cases; P < .01) mainly because of bacterial (80.0% versus 50.0%; P < .05) and viral (50.0% versus 16.6%; P < .05) agents. In conclusion, the study shows that intravenous administration of 1,000 mg of D espite the use of new and potent immunosuppressive regimens, rejection still remains one of the most important causes of graft failure and morbidity after liver transplantation. 1,2 The efficacy of the new and potent immunosuppressive agents in controlling rejection always has to be balanced against the increased risk of adverse effects. 3 Thus, maintenance immunosuppressive regimens are always a compromise between their efficacy and safety in clinical practice. As a consequence, episodes of acute cellular rejection can occur requiring additional immunosuppressive therapy for their treatment. The prevalence of clinically significant acute cellular rejection ranges from 24% to 80%. 4,5 Moreover, the prevalence of graft failure as a consequence of acute cellular rejection ranges from 5% to 15%. 4,5 In most transplant centers, high-dose corticosteroids are the mainstay for the treatment of acute hepatic cellular rejection in transplant recipients. In particular, they are used in the treatment of grade II and III acute hepatic cellular rejection because their spontaneous resolution seems to be unlikely. [6][7][8] Corticosteroids are preferred to other immunosuppressive agents in the treatment of acute cellular rejection after liver transplantation for their broad range of actions. They inhibit graft antigen-induced lymphocyte activation induc...

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A possible defect of guanosine 3Ј-5Ј-cyclic monophosphate (cGMP) content in the renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has, so far, not been evaluated in the pathogenesis of renal resistance to endogenous natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a specific cGMP-PDE inhibitor (30 g/kg/min). Moreover, the effects of the intravenous administration of Zaprinast (15 g/kg/min and 30 g/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR), and urinary sodium excretion (U Na V) were evaluated in 10 conscious control rats and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U Na V were evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity and increased the renal content of cGMP in these animals. The inhibition of cGMP-PDE was associated with an increase in RPF, GFR, and U Na V and a reduction in PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to the renal resistance to ENP in cirrhosis with ascites. (HEPATOLOGY 2000;31; 304-310.)Increased circulating levels of endogenous natriuretic peptides (ENP), a family of 4 distinct, but related substances 1 : atrial natriuretic peptide (ANP), 2 brain natriuretic peptide, 3 C-type natriuretic peptide, 4 and urodilatin 5 are hallmarks of patients with cirrhosis and ascites. 6-11 Although ENP were found to play an important role in the preservation of renal hemodynamics and sodium excretion in cirrhotic rats with ascites, 12 advanced stages of cirrhosis and ascites are characterized in animal models, as well as in patients with cirrhosis and ascites, by a reduced natriuretic and glomerular responsiveness to exogenous administration of ANP, brain natriuretic peptide, and C-type natriuretic peptide. [12][13][14][15][16] Several biological effects of ENP, including increased glomerular filtration and natriuresis, are mediated via 2 biologically active types of receptors, namely NPR-A and NPR-B receptors. [17][18][19][20] The downstream activation of a membrane guanylyl cyclase results in increased guanosine 3-Ј5Ј-cyclic monophosphate (cGMP) generation. [17][18][19][20][21] The mechanisms that mediate the renal hyporesponsiveness to ENP in cirrhosis with ascites remain poorly defined. They may be multifactorial and include the activation of renal vasoconstrictors and antinatriuretic factors, i.e., renin-...

Splenic Doppler impedance indices are influenced, in portal hypertensive patients, by the resistance of the portal system. The aim of the study was to verify the usefulness of these indices in evaluating the presence of a pathological increase in portal resistance in patients with complications after liver transplantation. Splenic impedance indices have been evaluated in 46 patients before orthotopic liver transplantation (OLT), and 2 days, 1, 4, 8, and 12 to 18 months after transplantation. The results showed that spleen size slowly decreased after liver transplantation. From a baseline longitudinal diameter value of 18.0 ؎ 3.6 cm (M ؎ SD), the decrease was by 0% ؎ 3%, 8% ؎ 8%, 13% ؎ 9%, 15% ؎ 11%, and 14% ؎ 11% at 2 days and 1, 4, 8, and 12 to 18 months after liver transplantation. Splenic impedance indices-resistance index ‫؍‬ (peak systolic ؊ end diastolic) / peak systolic velocity; pulsatility index ‫؍‬ (peak systolic ؊ end diastolic) / mean velocity-which were increased before liver transplantation, showed a rapid decrease to normal values: resistance index: from 0. The measurement of Doppler impedance indices (DIIs) is a simple and noninvasive method to evaluate alterations in arterial and venous hemodynamics associated with different pathological conditions. 1,2 These indices are mainly considered as parameters of arterial resistance, 2-4 but their interpretation varies according to the investigated organ. In particular, intra-splenic DIIs are influenced by venous congestion of the organ, as they are related to spleno-portal vascular resistance. 5 To confirm this, we have recently shown that splenic DIIs are higher on average in patients with cirrhosis and portal hypertension than in normal subjects, and they normalize after orthotopic liver transplantation (OLT). 5 The aim of the study was the evaluation of DIIs during the follow-up of patients with OLT, and of the relationships between these indices and the outcome of these patients thus establishing the clinical usefulness of the method. PATIENTS AND METHODSPatients. Forty-six patients (35 males and 11 females) with cirrhosis, who consecutively underwent OLT, were investigated. When OLT was performed, age of patients averaged 47 Ϯ 9 years (M Ϯ SD) (range 22-63). The cause of cirrhosis was alcoholic in 10 patients, posthepatitic in 23 (hepatitis B virus[HBV]-related in 7 patients, hepatitis C virus [HCV]-related in 15 patients, HBV-, HBC-, and hepatitis D virus [HDV]-related in 1 patient), mixed in 8 (HBV-related and alcoholic in 2 patients, HCV-related and alcoholic in 4 patients, HBV-and HCV-related, and alcoholic in 1 patient, HBV-and HDV-related and alcoholic in 1 patient), primary biliary in 3, secondary biliary in 2. According to Child-Pugh classification, 6 when they underwent OLT, 1 patient was class A, 31 patients were class B, and 14 were class C.All patients underwent a splanchnic duplex Doppler ultrasonography every 2 months, while they were on the waiting list for OLT. Therefore, baseline measurements were performed approxiamtely 1 month b...